BACKGROUND: Detailed descriptions of long-term persistence of human papillomavirus (HPV) in the absence of cervical precancer are lacking. METHODS: In a large, population-based natural study conducted in Guanacaste, Costa Rica, we studied a subset of 810 initially HPV-positive women with ≥ 3 years of active follow-up with ≥ 3 screening visits who had no future evidence of cervical precancer. Cervical specimens were tested for >40 HPV genotypes using a MY09/11 L1-targeted polymerase chain reaction method. RESULTS: Seventy-two prevalently-detected HPV infections (5%) in 58 women (7%) persisted until the end of the follow-up period (median duration of follow-up, 7 years) without evidence of cervical precancer. At enrollment, women with long-term persistence were more likely to have multiple prevalently-detected HPV infections (P < .001) than were women who cleared their baseline HPV infections during follow-up. In a logistic regression model, women with long-term persistence were more likely than women who cleared infections to have another newly-detected HPV infection detectable at ≥ 3 visits (odds ratio, 2.6; 95% confidence interval, 1.2-5.6). CONCLUSIONS: Women with long-term persistence of HPV infection appear to be generally more susceptible to other HPV infections, especially longer-lasting infections, than are women who cleared their HPV infections.